One new challenge for vaccine design is the development of effective vaccines for the ever growing geriatric population. Influenza is a highly contagious viral infection of the respiratory tract that afflicts 3-5 million people world-wide with 200,000-500,000 deaths each year. The elderly (>65 years) are especially prone to severe influenza infection. There is now strong evidence that the seasonal H1N1 influenza vaccine is largely ineffective for these elderly subjects, subjecting them to high risk of complication, hospitalization and death. The ineffectiveness of current flu vaccines in the elderly has been associated with immunosenescence, which is a gradual age-associated deterioration of the immune system. There is growing belief that some of the key limitations resulting in immunosenescence can be overcome by improved immunization strategies, such as the use of novel adjuvants to promote effective memory immunity. Current adjuvants typically work by activating dendritic cells (DCs) at the site of vaccine administration and enhancing the trafficking of antigen-loaded DCs to the draining lymph nodes (DLNs), the epicenter of the adaptive immune response and where antigen presentation to T cells occurs. Here, we propose an alternate strategy to accelerate and maximize the immune responses. We recently developed a particle-mediated vaccine system capable of transporting critical immunostimulatory cytokines directly to the DLN during vaccination. This adjuvant technology induced rapid and significant organizational changes to the DLNs of aged mice, animals that are not immunoresponsive, like their human counterparts. The changes in the DLNs induced by targeted delivery of these immunomodulators were consistent with robust immune responses, including vigorous and sustained recruitment of not only DCs but also T cells. The objective of this proposal is to develop an effective immune stimulatory strategy and adjuvant formulation with the potential of overcoming immunosenescence. The Specific aims are: 1) Optimize the composition, size and loading of biocompatible and degradable nanoparticles with various combinations of immunodulatory mediators to achieve maximal delivery and controlled release in the DLNs; 2) Demonstrate the safety and efficacy of a vaccine formulation comprising the seasonal Flu vaccine and various cytokine-loaded nanoparticles in promoting maximal immunity in aged mice; 3) Evaluate the prophylactic and therapeutic ability of the flu vaccine in combination with lymph node activating nanoparticles in protecting aged mice against lethal influenza virus infections. If proven successful, this approach could serve as a new paradigm for improving vaccines in general. PUBLIC HEALTH RELEVANCE: Relevance to Healthcare Many vaccines are ineffective in elderly patients (>65 years) because of immunosenescence, a gradual age-associated deterioration of the immune system. We have developed a particle- mediated adjuvant technology capable of delivering critical immunostimulatory cytokines directly to the draining lymph node, the epicenter of the adaptive immune response and where antigen presentation to T cells occurs. By accelerating and maximizing the immune responses to previously non-responsive subpopulations, this vaccine technology may significantly improve the healthcare of elderly patients.